Frontotemporal dementia (FTD) is a group of heterogeneous sporadic and familial neurodegenerative disorders. Approximately half of the patients with FTD develop abundant tau pathologies in neurons and glia. The familial counterpart of this group of FTDs is known as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) which includes patients with phenotypes similar to sporadic disorders like progressive supranuclear palsy (PSP), Pick's disease (PiD), cortical basal degeneration (CBD), and argyrophilic grains disease (AGD). In contrast to FTD characterized by prominent tau pathologies, the brains of the remaining FTD patients either lack distinctive neuropathological lesions, referred to as dementia lacking distinctive histopathology (DLDH) or show ubiquitin-positive, but tau and alpha-synuclein (alpha-syn) negative inclusions with or without motor neuron disease (FTD-MND). To clarify similarities and differences among mechanisms underlying FTDs, the goals of Project 3 are to characterize the neuropathology of FTDs using biochemical, immunohistochemical and ultrastructural methods with specific emphasis on testing the hypothesis that cofactors such as alpha-syn, heparan sulfate, or oxidants play distinct roles in regulating tau pathologies including the isoform composition of tau lesions. Other studies will determine if amino or carboxy-terminal truncated tau fragments serve as "seeds" to facilitate tau fibrillization. Finally, to further investigate the etiology and pathogenesis of distinct FTDs, Project 3 also will examine FTD-MND by isolating the ubiquitin-positive, tau and alpha-syn negative inclusions and determining the protein building blocks of these inclusions. Successful completion of the studies proposed in Project 3 will address fundamental disease mechanisms of FTDs, which, in conjunction with research advances from other projects in this Program Project Grant will accelerate efforts to find better therapeutic interventions for patients with diverse FTDs.